Method for the production of imidazo-(1,2-C)(2,3)-benzodiazepines and intermediates in the production thereof

ABSTRACT

The invention relates to a method for the preparation of compound of formula (1). The invention further relates to the previously unknown compounds of formulas (5 and 6) as intermediates in the production of benzodiazepines of formula (1).

[0001] The invention relates to a new process for the production ofimidazo[1,2-c][2,3]benzodiazepines of general formula (1) as well as newintermediate products in the process,

[0002] in which

[0003] R¹=hydrogen, C₁-C₆-alkyl, nitro, halogen, cyano, C₁-C₄-alkoxy,—CF₃, hydroxy or C₁-C₆-alkanoyloxy,

[0004] R² and R³ are the same or different and mean hydrogen, halogen,C₁-C₆-alkoxy, hydroxy, cyano, C₁-C₆-alkanoyl, C₂-C₆-alkynyl,C₂-C₆-alkenyl; C₁-C₆-alkyl or C₃-C₇-cycloalkyl optionally substituted byhalogen, hydroxy or C₁₋₆-alkoxy; or an aryl or hetaryl radical that isoptionally substituted by halogen, C₁₋₄-alkoxy or C₁₋₄-alkyl,

[0005] X=hydrogen or halogen,

[0006] Y=C₁-C₆-alkoxy, or

[0007] X and Y together mean —O—(CH₂)_(n)—O— with

[0008] n=1, 2 or 3.

[0009] The invention also contains, as new intermediate products for theproduction of pharmacologically active compounds, phenylacetic acidderivatives of general formula 5,

[0010] in which

[0011] R¹=hydrogen, C₁-C₆-alkyl, nitro, halogen, cyano, C₁-C₄-alkoxy,—CF₃, hydroxy or C₁-C₆-alkanoyloxy,

[0012] R² and R³ are the same or different and mean hydrogen, halogen,C₁-C₆-alkoxy, hydroxy, cyano, C₁-C₆-alkanoyl, C₂-C₆-alkynyl,C₂-C₆-alkenyl; C₁-C₆-alkyl or C₃-C₇-cycloalkyl optionally substituted byhalogen, hydroxy or C₁₋₆-alkoxy, or an aryl or hetaryl radical that isoptionally substituted with halogen, C₁₋₄-alkoxy or C₁₋₄-alkyl,

[0013] X=hydrogen or halogen,

[0014] Y=C₁-C₆-alkoxy or

[0015] X and Y together mean —O—(CH₂)_(n)—O— with

[0016] n=1, 2 or 3, and

[0017] oxazole derivatives of general formula 6,

[0018] in which

[0019] R¹=hydrogen, C₁-C₆-alkyl, nitro, halogen, cyano, C₁-C₄-alkoxy,—CF₃, hydroxy or C₁-C₆-alkanoyloxy,

[0020] R² and R³ are the same or different and mean hydrogen, halogen,C₁-C₆-alkoxy, hydroxy, cyano, C₁-C₆-alkanoyl, C₂-C₆-alkynyl,C₂-C₆-alkenyl; C₁-C₆-alkyl or C₃-C₇-cycloalkyl optionally substituted byhalogen, hydroxy or C₁₋₆-alkoxy, or an aryl or hetaryl radicaloptionally substituted by halogen, C₁₋₄-alkoxy or C₁₋₄-alkyl,

[0021] X=hydrogen or halogen,

[0022] Y=C₁-C₆-alkoxy or

[0023] X and Y together mean —O—(CH₂)_(n)—O— with

[0024] n=1, 2 or 3.

[0025] The radicals within the general formulas have the followingmeanings:

[0026] C₁-C₆-Alkyl is defined in each case as a straight-chain orbranched alkyl radical, such as, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl or hexyl.

[0027] R² and R³ in the meaning of C₂-C₆-alkenyl contain, in each case,at least one double bond, such as, for example, vinyl, propenyl,buten-1-yl, isobutenyl, penten-1-yl, 2,2-dimethyl-buten-1-yl,3-methylbuten-1-yl, or hexen-1-yl.

[0028] If R² and R³ mean C₁-C₆-alkynyl, at least one triple bond ispresent, such as, for example, ethynyl, propynyl, butyn-1-yl,butyn-2-yl, pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, or hexyn-1-yl.Tne above-described alkenyl or alkinyl radicals can optionally also besubstituted with halogen atoms. If a halogenated alkyl radical ispresent, the latter can be halogenated in one or more places, but canalso be perhalogenated, such as, for example, —CF₃.

[0029] Within the above radicals, halogen is defined respectively asfluorine, chlorine, bromine and iodine.

[0030] R² and R³ in the meaning of aryl and hetaryl radicals canoptionally be substituted in one, two or three places with halogen,C₁₋₄-alkoxy-, or C₁₋₄-alkyl radicals; any permutations are possible.

[0031] The aryl and hetaryl radicals can be present as monocyclic orbicyclic compounds and contain 5-12 ring atoms, preferably 5-9 ringatoms, such as, for example, phenyl, biphenyl, naphthyl, or indenyl asan aryl radical, and thienyl, furyl, pyranyl, pyrrolyl, pyrazolyl,pyridyl, pyrimidyl, pyridazinyl, oxazolyl, isooxazolyl, thiazolyl,isothioazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl,1,2,4-oxadiazol-3-yl, quinolyl, isoquinolyl, benzo[1]thienyl, orbenzofuranyl as a hetaryl radical, containing 1-3 heteroatoms, such as,for example, sulfur, oxygen, and/or nitrogen. As preferred radicals,2-thienyl, 3-thienyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl andphenyl can be mentioned.

[0032] With R² and R³ in the meaning of C₃-C₈-cycloalkyl, for example,the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptylradicals are meant.

[0033] As C₁-C₆-alkanoyl radicals, in each case straight-chaih orbranched aliphatic carboxylic acid radicals, such as, for example,formyl, acetyl, propinoyl, butanoyl, isopropylcarbonyl, caproyl,valeroyl or trimethylacetyl, are suitable.

[0034] R¹ preferably means hydrogen, chlorine, nitro, methoxy; R² and R³preferably mean hydrogen, or C₁₋₄-alkyl or phenyl; X and Y togetherpreferably mean —O—CH₂—O—.

[0035] Processes for the production of the compounds of general formula1 are described within WO 97/28163.

[0036] The object of this invention is a new process for the synthesisof the compounds of general formula 1. Subjects of this invention arealso new, previously unknown intermediate products of general formulas 5and 6, which are processed within the framework of the synthesis and canbe used per se or derivatized as starting materials for the synthesis ofother target molecules.

[0037] This object is achieved by the teaching of the claims.

[0038] By the process according to the invention, fewer intermediatestages are processed than in the known synthesis from the prior art, thenumber of purification steps is significantly lower and the total yieldis increased. The process according to the invention makes possible theproduction of the compounds of formula I on an industrial scale.

[0039] The invention thus contains a process for the production ofimidazo[1,2-c][2,3]benzodiazepines of general formula 1

[0040] in which R¹, R² and R³ as well as X and Y have the above meaning,

[0041] from phenylacetic acids of general formula 4,

[0042]  in which X, Y and R¹ have the above-mentioned meaning

[0043] a) by esterification with an alcohol of Formula 5 a

[0044]  to form phenylethyl acetate of general formula 5,

[0045]  in which

[0046] X, Y, R¹, R² and R³ have the above-mentioned meaning,

[0047] b) by condensation with ammonia or an ammonia donor to form theoxazole of general formula 6,

[0048]  in which

[0049] X, Y, R¹, R² and R³ have the above-mentioned meaning, andsubsequent hydrazinolysis to form the compounds of general formula 1.

[0050] Imidazo[1,2-c][2,3]benzodiazepines of general formula 1 aresynthesized according to Diagram 1.

[0051] The reaction of a compound of general formula 2 to form acompound of general formula 3 is carried out according to a process thatis known in the art (e.g., J. Chem. Soc., Perkin Trans. 1 1991, 169-173)of a Friedel-Crafts reaction. For example, compounds of general formula2 are reacted in the presence of Lewis acids, such as, for example, tintetrachloride, aluminum trichloride, titanium tetrachloride and anacylating agent, such as, for example, benzoyl chloride, benzoic acidanhydride or another activated carboxylic acid derivative. A significantincrease in yield is achieved if additional N,N-dimethyl acetamide isadded to the reaction mixture. As a solvent, halogenated hydrocarbons,such as, e.g., methylene chloride or ethylene chloride and mixturesthereof can be used. The reaction is performed in a temperature range of−30° to 50° C., but preferably in a temperature range of 0° to 25° C.

[0052] The reaction of a compound of general formula 3 to form acompound of general formula 4 is carried out according to a process of asaponification reaction that is known in the art. For example, acompound of general formula 3 is heated in the presence of a base, suchas alkali hydroxide, but preferably sodium hydroxide, in a solvent, suchas a lower, preferably primary alcohol or water or mixtures thereof. Thereaction is performed in a temperature range of 25° to 150° C., butpreferably in the temperature range of 70° to 110° C.

[0053] The reaction of a compound of general formula 4 to form acompound of formula 5 is carried out according to a process of anesterification that is known in the art. For example, a compound ofgeneral formula 4 is reacted in the presence of an activating reagent,such as, e.g., carbonyldiimidazole, and an alcohol of formula

[0054] such as 3-hydroxy-2-butanone. As solvents, halogenatedhydrocarbons, such as, e.g., methylene chloride or ethylene chloride, aswell as THF and mixtures thereof can be used. The reaction is performedin a temperature range of −20° to 100° C., but preferably in atemperature range of 0° to 25° C.

[0055] It is familiar to one skilled in the art that R² and R³ can bevaried in compounds of general formula 5 according to standard methods.This can take place by use of other alcohols in the esterification step,but also by reesterification of an ester that is already present. R² andR³ can thus have the meaning of hydrogen, halogen, alkoxy, hydroxy,cyano, alkanoyl, optionally substituted alkynyl, optionally substitutedalkenyl; alkyl or cycloalkyl that is optionally substituted by halogen,hydroxy, or alkoxy; or an optionally substituted aryl or hetarylradical.

[0056] The reaction of a compound of general formula 5 to form acompound of general formula 6 is carried out according to a process,known in the art, for the production of oxazoles by condensation of twocarbonyl groups with ammonia. For example, a compound of general formula5 is reacted in the presence of ammonium acetate, ammonia, an ammoniasolution or another ammonia donor, such as, e.g., acetamide or formamidein the presence of acetic acid. As solvents, halogenated hydrocarbons,such as, e.g., methylene chloride or ethylene chloride; organic acids,such as e.g., formic acid or acetic acid, as well as lower alcohols,such as, e.g., methanol or ethanol, but also ethylene glycol andmixtures thereof, can be used. The reaction is performed in atemperature range of 0° to 150° C., but preferably in a temperaturerange of 50° to 100° C.

[0057] The reaction of a compound of general formula 6 to form acompound of general formula 1 is carried out according to a process,known in the art, by hydrazinolysis or hydrazone formation. For example,a compound of general formula 6 is reacted in the presence of hydrazineor hydrazine-hydrate. As solvents, halogenated hydrocarbons, such as,e.g., methylene chloride or ethylene chloride, organic acids, such as,e.g., formic acid or acetic acid, as well as lower alcohols, such as,e.g., methanol or ethanol, but also ethylene glycol and mixturesthereof, are used. The reaction is performed in a temperature range of0° to 200° C., but preferably in a temperature range of 80° to 120° C. Areaction scheme in an autoclave is possible.

[0058] The reaction of a compound of general formula 5 to form acompound of formula 1 is also carried out in a single-pot reaction. Forexample, a compound of formula 5 is reacted in the presence of ammoniumacetate, ammonia, an ammonia solution or another ammonia donor, such as,e.g., acetamide or formamide in the presence of acetic acid. Assolvents, halogenated hydrocarbons, such as, e.g., methylene chloride orethylene chloride; organic acids, such as, e.g., formic acid or aceticacid, as well as lower alcohols, such as, e.g., methanol or ethanol; butalso ethylene glycol and mixtures thereof can be used. The reaction isperformed in a temperature range of 0° to 150° C., but preferably in atemperature range of 50° to 100° C. After the reaction is completed,hydrazine or hydrazine-hydrate is added to the reaction mixture. Thereaction is performed in a temperature range of 0° to 200° C., butpreferably in a temperature range of 80° to 120° C. A reaction scheme inan autoclave is possible.

[0059] If the production of the starting compounds is not described, thelatter are known or can be produced analogously to known processes or toprocesses that are described here. Below, the process according to theinvention is depicted by way of example.

EXAMPLES 2-Benzoyl-4,5-(methylenedioxy)-phenylacetic Acid Methyl Ester(3)

[0060] 79 ml of tin tetrachloride and 25 ml of N,N′-dimethylacetamide in270 ml of methylene chloride are mixed at room temperature with 39 ml ofbenzoyl chloride. 44 g of 4,5-(methylenedioxy)-phenylacetic acid methylester (2) is added in drops to this mixture at 0° C., and the solutionis stirred for 12 hours at room temperature. For the purpose ofworking-up, the addition of 660 ml of water at −15° C. as well as anextraction of the aqueous phase with methylene chloride follow. Thecollected organic fractions are washed with 6N aqueous NaOH andcompletely concentrated by evaporation in a rotary evaporator. Crudeproduct 3 (74 g) is crystallized from ethanol.

[0061]¹H-NMR (CDCl₃): δ=3.61 (s, 3 H, OMe), 3.80 (s, 2 H, benzyl. CH₂),6.03 (s, 2 H, OCH₂O), 6.84 and 6.88 (2 s to 1 H, 3- and 6-H aryl),7.43-7.80 (m, 5 H, PhCO). Melting point: 74-76° C., combustion analysis:Cld. C 68.45 H 4.73 Fnd. C 68.53 H 4.59

[0062] Produced analogously are:

[0063] 2-(4-Chloro-benzoyl)-4,5-(methylenedioxy)-phenylacetic acidmethyl ester

[0064] 2-(4-Nitro-benzoyl)-4,5-(methylenedioxy)-phenylacetic acid methylester

[0065] 2-(4-Methoxy-benzoyl)-4,5-(methylenedioxy)-phenylacetic acidmethyl ester

[0066] 2-(4-Methyl-benzoyl)-4,5-(methylenedioxy)-phenylacetic acidmethyl ester

[0067] 2-(4-Cyano-benzoyl)-4,5-(methylenedioxy)-phenylacetic acid methylester

2-Benzoyl-4,5-(methylenedioxy)-phenylacetic Acid (4)

[0068] A suspension of 10 g of 2 in 50 ml of 1N aqueous NaOH is refluxedfor 2 hours. Then, 10 ml of 1N aqueous sulfur acid is added, and theprecipitating solid is filtered off and rewashed with water. Product 4(8.3 g) is dried i.v. and used without further purification in the nextstage.

[0069]¹H-NMR (DMSO): δ=3.68 (s, 2 H, benzyl. CH₂), 6.12 (s, 2 H, OCH₂O),6.86 and 7.03 (2 s to 1 H, 3- and 6-H aryl), 7.50-7.73 (m, 5 H, PhCO),12.18 (br. s, 1 H, COOH). Melting point: 185-189° C., combustionanalysis: Cld. C 67.60 H 4.25 Fnd. C 67.66 H 4.20

[0070] Produced analogously are:

[0071] 2-(4-Chloro-benzoyl)-4,5-(methylenedioxy)-phenylacetic acid

[0072] 2-(4-Nitro-benzoyl)-4,5-(methylenedioxy)-phenylacetic acid

[0073] 2-(4-Methoxy-benzoyl)-4,5-(methylenedioxy)-phenylacetic acid

[0074] 2-(4-Methyl-benzoyl)-4,5-(methylenedioxy)-phenylacetic acid

[0075] 2-(4-Cyano-benzoyl)-4,5-(methylenedioxy)-phenylacetic acid

2-Benzoyl-4,5-(methylenedioxy)-phenylacetic Acid-(3-oxo-but-2-ylester)(5)

[0076] 50 g of 4, 19 g of 3-hydroxy-2-butanone and 32 g ofN,N′-carbonyldiimidazole are dissolved at room temperature in 500 ml ofmethylene chloride and stirred for 3 days. For working-up, it is mixedwith 200 ml of VE-water and then extracted with methylene chloride. Thecollected organic fractions are concentrated by evaporation in a rotaryevaporator. The crude product is crystallized from methanol (2×), and 45g of 5 is obtained.

[0077]¹H-NMR (CDCl₃): δ=1.32 (d, 3 H, J=6.9, CH₃C—O), 2.11 (s, 3 H,CH₃C═O), 3.88 (s, 2 H, benzyl. CH₂), 5.03 (q, 1 H, J=6.9, CH—O), 6.04(s, 2 H, OCH₂O), 6.87 and 6.90 (2 s to 1 H, 3- and 6-H aryl), 7.42-7.74(m, 5 H, PhCO). Melting point: 81-83° C., combustion analysis: Cld. C67.79 H 5.12 Fnd. C 67.83 H 5.04

[0078] Produced analogously are:

[0079] 2-(4-Chloro-benzoyl)-4,5-(methylenedioxy)-phenylaceticacid-(3-oxo-but-2-ylester)

[0080] 2-(4-Nitro-benzoyl)-4,5-(methylenedioxy)-phenylaceticacid-(3-oxo-but-2-ylester)

[0081] 2-(4-Methoxy-benzoyl)-4,5-(methylenedioxy)-phenylaceticacid-(3-oxo-but-2-ylester)

[0082] 2-Benzoyl-4,5-(methylenedioxy)-phenylaceticacid-(4-oxo-hex-3-ylester)

[0083] 2-Benzoyl-4,5-(methylenedioxy)-phenylaceticacid-(2-oxo-1,2-diphenyl-eth-1-ylester)

2-Benzoyl-4,5-(methylenedioxy)-benzyl-4,5-dimethyl-oxazole (6)

[0084] 14 ml of concentrated acetic acid is added to 10 g of 5 and 19 gof ammonium acetate in 200 ml of 1,2-dichlorethane, and the mixture isrefluxed for 6 hours. Then, 100 ml of 1N aqueous NaOH is added, and itis extracted with methylene chloride. The combined organic extracts areconcentrated by evaporation in a rotary evaporator, and the crudeproduct is filtered on silica gel (hexane:ethyl acetate 9:1→8:2). 6.9 gof pure 6 is obtained (viscous oil).

[0085]¹H-NMR (CDCl₃): δ=1.94 and 2.03 (2 s to 3 H, 2 CH₃), 4.13 (s, 2 H,benzyl, CH₂), 6.01 (s, 2 H, OCH₂O), 6.83 and 6.86 (2 s to 1 H, 3- and6-H aryl), 7.41-7.80 (m, 5 H, PhCO). Combustion analysis: Cld. C 71.63 H5.11 N 4.18 Fnd. C 71.47 H 5.04 N 3.97

[0086] Produced analogously are:

[0087]2-(4-Chloro-benzoyl)-4,5-(methylenedioxy)-benzyl-4,5-dimethyl-oxazole

[0088]2-(4-Nitro-benzoyl)-4,5-(methylenedioxy)-benzyl-4,5-dimethyl-oxazole

[0089]2-(4-Methoxy-benzoyl)-4,5-(methylenedioxy)-benzyl-4,5-dimethyl-oxazole

[0090] 2-Benzoyl-4,5-(methylenedioxy)-benzyl-4,5-diethyl-oxazole

[0091] 2-Benzoyl-4,5-(methylenedioxy)-benzyl-4,5-diphenyl-oxazole

2,3-Dimethyl-6-phenyl-(12H)-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine(1)

[0092] In an autoclave, 0.5 ml of hydrazine-hydrate is added to 2 g of6, dissolved in 18 ml of ethylene glycol and 2 ml of concentrated aceticacid. It is heated for 12 hours to 120° C., and then the reactionmixture is mixed at room temperature with 2N aqueous NaOH. It isextracted several times with ethyl acetate, and the combined organicphases are completely concentrated by evaporation in a rotaryevaporator. The crude product is purified by column chromatography(hexane: ethyl acetate 9:1→8:2), and the yield of pure 1 is 1.2 g.

[0093]¹H-NMR (DMSO): δ=2.01 and 2.20 (2 s to 3 H, 2 CH₃), 3.82 (br. s, 2H, benzyl, CH₂), 6.08 (s, 2 H, OCH₂O), 6.55 and 7.15 (2 s to 1 H, 2aryl-H), 7.48-7.72 (m, 5 H, PhCO). Melting point: 177° C., combustionCld. C 72.49 H 5.18 N 12.88 analysis: Fnd. C 72.33 H 5.31 N 12.46

[0094] Produced Analogously are:

[0095]2,3-Dimethyl-6-(4-chloro-phenyl)-(12H)-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0096]2,3-Dimethyl-6-(4-nitro-phenyl)-(12H)-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0097]2,3-Dimethyl-6-(4-methoxy-phenyl)-(12H)-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0098]2,3-Diethyl-6-phenyl-(12H)-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

[0099]2,3-Diphenyl-6-phenyl-(12H)-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine

1. Process for the production of imidazo[1,2-c][2,3]benzodiazepines ofgeneral formula 1

in which R¹=hydrogen, C₁-C₆-alkyl, nitro, halogen, cyano, C₁-C₄-alkoxy,—CF₃, hydroxy or C₁-C₆-alkanoyloxy, R² and R³ are the same or differentand mean hydrogen, halogen, C₁-C₆-alkoxy, hydroxy, cyano,C₁-C₆-alkanoyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl; C₁-C₆-alkyl orC₃-C₇-cycloalkyl optionally substituted by halogen, hydroxy orC₁₋₆-alkoxy, or an aryl or hetaryl radical that is optionallysubstituted by halogen, C₁₋₄-alkoxy or C₁₋₄-alkyl, X=hydrogen orhalogen, Y=C₁-C₆-alkoxy or X and Y together mean —O—(CH₂)_(n)—O— withn=1, 2 or 3, from phenylacetic acids of general formula 4,

in which X, Y and R¹ have the above-mentioned meaning, a) byesterification with an alcohol of formula 5a

 to form phenylethyl acetate of general formula 5,

in which X, Y, R¹, R² and R³ have the above-mentioned meaning, b) bycondensation with ammonia or an ammonia donor to form the oxazole ofgeneral formula 6,

in which X, Y, R¹, R² and R³ have the above-mentioned meaning, andsubsequent hydrazinolysis to form the compounds of general formula 1

in which X, Y, R¹, R² and R³ have the above-mentioned meaning. 2.Process according to claim 1, whereby compounds of general formula 5 arereacted using a single-pot reaction by reaction in the presence ofammonium acetate and ammonia or an ammonia donor at 0-150° C. in thesolvent or solvent mixtures and then with hydrazine at 0-200° C.,optionally in autoclaves in which compounds of general formula 1 arereacted.
 3. Process according to claim 1 or 2 for the production of2,3-dimethyl-6-phenyl-(12H)-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine2,3-Dimethyl-6-(4-chloro-phenyl)-(12H)-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine2,3-Dimethyl-6-(4-nitro-phenyl)-(12H)-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine2,3-Dimethyl-6-(4-methoxy-phenyl)-(12H)-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine2,3-Diethyl-6-phenyl-(12H)-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine2,3-Diphenyl-6-phenyl-(12H)-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine4. Phenylacetic acid ester of general formula 5,

in which R¹=hydrogen, C₁-C₆-alkyl, nitro, halogen, cyano, C₁-C₄-alkoxy,—CF₃, hydroxy or C₁-C₆-alkanoyloxy, R² and R³ are the same or differentand mean hydrogen, halogen, C₁-C₆-alkoxy, hydroxy, cyano,C₁-C₆-alkanoyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl; C₁-C₆-alkyl orC₃-C₇-cycloalkyl optionally substituted by halogen, hydroxy orC₁₋₆-alkoxy; or an aryl or hetaryl radical that is optionallysubstituted by halogen, C₁₋₄-alkoxy or C₁₋₄-alkyl, X=hydrogen orhalogen, Y=C₁-C₆-alkoxy or X and Y together mean —O—(CH₂)_(n)—O— withn=1, 2 or
 3. 5. Oxazole derivatives of general formula 6,

in which R¹=hydrogen, C₁-C₆-alkyl, nitro, halogen, cyano, C₁-C₄-alkoxy,—CF₃, hydroxy or C₁-C₆-alkanoyloxy, R² and R³ are the same or differentand mean hydrogen, halogen, C₁-C₆-alkoxy, hydroxy, cyano,C₁-C₆-alkanoyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl; C₁-C₆-alkyl orC₃-C₇-cycloalkyl optionally substituted by halogen, hydroxy orC₁₋₆-alkoxy; or an aryl or hetaryl radical optionally substituted byhalogen, C₁₋₄-alkoxy or C₁₋₄-alkyl, X=hydrogen or halogen,Y=C₁-C₆-alkoxy or X and Y together mean —O—(CH₂)_(n)—O— with n=1, 2 or3.